Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles

ABSTRACT

Novel heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles, useful as intermediates and as antifungal and antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 224,992, filed Jan. 14, 1981,now U.S. Pat. No. 4,368,200, which in turn is a division of applicationSer. No. 20,383, filed Mar. 14, 1979, now U.S. Pat. No. 4,267,179, whichin turn is a continuation-in-part of application Ser. No. 919,333, filedJune 23, 1978, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 3,936,470 and Belg. Pat. No. 837,831 there aredescribed a number of 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles and1H-1,2,4-triazoles having antifungal and antibacterial properties. Thecompounds of this invention differ from the foregoing essentially by thesubstitution of the aryloxy-moiety with a 4-phenylpiperazinyl group,wherein said phenyl is further substituted with a heterocyclic radicalwhich is attached to the phenyl group by a carbon-nitrogen bond. Similarcompounds wherein a heterocyclic radical is attached directly to thearyloxy group by a carbon-nitrogen bond are described in U.S. patentapplication Ser. No. 853,726, filed Nov. 21, 1977 now U.S. Pat. No.4,160,841.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with novel 1H-imidazole and1H-1,2,4-triazole derivatives which may structurally be represented bythe formula: ##STR1## and the pharmaceutically acceptable acid additionsalts and stereochemically isomeric forms thereof, wherein:

Q is a member selected from the group consisting of CH and N;

Ar is a member selected from the group consisting of phenyl, thienyl,halothienyl and substituted phenyl, said substituted phenyl having from1 to 3 substituents each independently selected from the groupconsisting of halo, lower alkyl, lower alkyloxy and trifluoromethyl; and

the radical Y is a member selected from the group consisting of

a 1H-pyrrol-1-yl radical of the formula ##STR2## wherein R¹, R², R³ andR⁴ are each independently selected from the group consisting ofhydrogen, lower alkyl, aryl and aryl-lower alkyl;

a 1H-pyrazol-1-yl radical of the formula ##STR3## wherein R⁵, R⁶ and R⁷are each independently selected from the group consisting of hydrogen,lower alkyl, aryl and aryl-lower alkyl;

a 1H-imidazol-1-yl radical of the formula ##STR4## wherein R⁸ isselected from the group consisting of hydrogen, lower alkyl, mercapto,lower alkylthio and aryl-lower alkylthio, and R⁹ and R¹⁰ are eachindependently selected from the group consisting of hydrogen, loweralkyl, aryl and aryl-lower alkyl;

a 1H-1,2,4-triazol-1-yl radical of the formula ##STR5## wherein eitherof R¹¹ and R¹² is selected from the group consisting of hydrogen,hydroxy, mercapto, lower alkylthio and aryl-lower alkylthio, theremaining being selected from the group consisting of hydrogen, loweralkyl and aryl-lower alkyl;

a 4H-1,2,4-triazol-4-yl radical of the formula ##STR6## wherein R¹³ isselected from the group consisting of hydrogen, mercapto, hydroxy, loweralkylthio and aryl lower alkylthio, and R¹⁴ is selected from the groupconsisting of hydrogen lower alkyl, aryl and aryl-lower alkyl;

a 2,3-dihydro-4H-1,2,4-triazol-4-yl radical of the formula ##STR7##wherein R¹⁵ is selected from the group consisting of lower alkyl andaryl-lower alkyl and R¹⁶ is selected from the group consisting ofhydrogen, lower alkyl, and aryl-lower alkyl;

a 1H-1,2,3,4-tetrazol-1-yl radical of the formula ##STR8## wherein R¹⁷is selected from the group consisting of hydrogen, mercapto, loweralkyl, aryl and aryl-lower alkyl;

wherein said aryl as used in the foregoing definitions is selected fromthe group consisting of phenyl and substituted phenyl, said substitutedphenyl having from 1 to 3 substituents each independently selected fromthe group consisting of halo, lower alkyl, lower alkyloxy andtrifluoromethyl.

It is understood that radicals of formulas (c) and (g) wherein R⁸,respectively R¹⁷, stand for mercapto, as well as radicals of formulas(d) and (e) wherein R¹¹ or R¹², respectively R¹³, stand for mercapto orhydroxy, may also exist in their tautomeric thioxo, respectively oxo,forms. Such thioxo and oxo forms, although not explicitely indicated inthe above structures, are naturally intended to be within the scope offormula (I).

The preferred compounds of this invention are those where the4-phenylpiperazinyl function is attached to the phenoxymethyl moiety inthe para position.

As used in the foregoing and in following definitions the term "halo" isgeneric to fluoro, chloro, bromo and iodo; and "lower alkyl" is meant toinclude straight and branched hydrocarbon radicals having from 1 to 6carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl,pentyl, hexyl and the like.

In order to simplify the structural representation of the compounds (I)and of certain starting materials and intermediates used in thepreparation thereof, the 2-Ar-2-(1H-imidazol-1-ylmethyl or1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl group, wherein Ar is aspreviously defined, will hereafter be represented by the symbol D:##STR9##

The compounds of formula (I) wherein Y is as previously defined, butother than a radical of formula (c) or (g) wherein R⁸, respectively R¹⁷,is mercapto and other than a radical of formula (d) or (e) wherein R¹¹or R¹², respectively R¹³, is mercapto or hydroxy, said Y beingrepresented by Y' and said compounds being represented by the formula(I'), can be prepared by O-alkylating an appropriate phenol of formula(III) with a reactive ester of formula (II). ##STR10## In formula (II),W has the meaning of a reactive ester residue such as, for example,halo, preferably chloro, bromo or iodo, or a sulfonyloxy group such as,for example, methylsulfonyloxy or 4-methylphenylsulfonyloxy and thelike.

The reaction of (II) with (III) is carried out under art-knownconditions of performing O-alkylations with reactive esters. Thereaction is generally carried out in an appropriate reaction-inertorganic solvent such as, for example, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphorictriamide, dimethylsulfoxide,4-methyl-2-pentanone and the like, optionally in admixture with otherreaction-inert solvents such as, for example, aromatic hydrocarbons,e.g., benzene, methylbenzene, dimethylbenzene and the like. Further itis advantageous to add to the reaction mixture an appropriate base suchas, for example, an alkali metal hydride or carbonate, in order toenhance the rate of the reaction. Otherwise it may be advantageous tofirst convert the substituted phenol (III) into a metal salt thereof,preferably the sodium salt, in the usual manner, e.g., by the reactionof (III) with metal bases such as sodium hydride, sodium hydroxide andthe like, and to use thereafter said metal salt in the reaction with(II). Somewhat elevated temperatures are appropriate to enhance thereaction rate and most preferably the reaction is carried out at fromabout 80° C. to about 130° C.

The compounds of formula (I), wherein Y is as previously defined, cangenerally be prepared by cyclizing an intermediate of formula (IV) withan appropriately substituted aminobenzene of formula (V). ##STR11## Thereaction is carried out by stirring the reactants together in thepresence of an appropriate polar solvent, e.g., water, in admixture withan appropriate water-miscible organic solvent such as, for example,2-propanol, 2-propanone and the like, preferably at an elevatedtemperature, in order to enhance the rate of the reaction, and, mostpreferably, in the presence of an appropriate alkali- or earth alkalimetal iodide such as, for example, potassium iodide.

The compounds of formula (I) can alternatively be prepared byN-alkylating a compound of formula (VI) with an appropriatelysubstituted halo-benzene of formula (VII), following standardN-alkylating procedures. ##STR12## Said N-alkylation may be carried outin the usual manner, e.g., by stirring the reactants together,preferably at somewhat elevated temperatures in an appropriate organicsolvent such as, for example, dimethylsulfoxide, dimethylformamide andthe like, in the presence of an appropriate base such as, for example,an alkali metal hydride or carbonate.

Still another method of preparing the compounds of formula (I) is bycyclizing an appropriate intermediate of formula (VIII), wherein A is anamino group or a suitable derivative thereof, with an appropriatecyclizing agent, following art-known procedures, and, if desired,introducing substituents into the thus obtained heterocyclic compounds.##STR13## The nature of A in formula (VIII), as well as the nature ofthe cyclizing agent to be used in the cyclization step, depend upon themeaning of Y in the desired compounds (I) as will be explained hereafterin more detail.

The compounds of formula (I) wherein Y stands for the radical (a),wherein R¹, R², R³ and R⁴ have the previously defined meaning, saidcompounds being represented by the formula (I-a), can be derived from anappropriate amine of formula (VIII-a), by cyclizing the latter with anappropriate dione of formula (IX-a) or a tetrahydro-2,5-di(loweralkyloxy)furan of formula (IX-b). ##STR14##

The reaction of (VIII-a) with (IX-a) is conveniently carried out bystirring and refluxing the reactants together in an appropriate solvent,e.g., a lower alkanol such as ethanol and the like, preferably, but notnecessary, in the presence of an appropriate base such as, for example,an alkali metal carbonate, e.g., potassium carbonate and the like.

The reaction of (VIII-a) with (IX-b) is preferably carried out in apolar solvent, e.g., acetic acid and the like.

The compounds of formula (VIII-a), used as intermediates herein, displaystrong antifungal and antibacterial properties themselves and both asuseful intermediates herein and an antifungal and antibacterialsubstances they constitute an additional feature of this invention.

The compounds of formula (I) wherein Y stands for the radical (b),wherein R⁵, R⁶ and R⁷ have the previously defined meaning, saidcompounds being represented by the formula (I-b), can be derived from anappropriate hydrazine of the formula (VIII-b), which is usually employedin the form of an acid addition salt, by cyclizing the latter with anappropriate dione of formula (X). ##STR15## The reaction of (VIII-b)with (X) is carried out following the same procedure as for thepreparation of (I-a) starting from (VIII-a) and (IX-a). When R⁵ ishydrogen, the adjacent carbonyl group of (X) is preferably acetalizedprior to reacting said (X) with (VIII-b) in order to obtain a pyrazolederivative wherein R⁶ is unambigously located at the 5-position.Mixtures of position isomers which can otherwise be obtained when usingunacetalized aldehydes or ketones of formula (X) may be subjected tostandard isolation and purification procedures to separate the pureconstituents from each other.

The compounds of formula (I) wherein Y stands for a radical (c) whereinR⁹ and R¹⁰ are as previously defined and wherein R⁸ stands for mercapto,said compounds being represented by the formula (I-c-1), can be preparedby cyclizing an appropriate isothiocyanate of formula (VIII-c) with anappropriate amino-ethanone or aminoacetaldehyde of formula (XI).##STR16## The reaction of (VIII-c) with (XI) is conveniently carried outby stirring, preferably under heating, the reactants together in asuitable organic solvent, such as a lower alcohol, e.g., 2-propanol, inthe presence of an appropriate base such as, for example, an alkali orearth alkali metal carbonate or hydrogen carbonate.

The compounds of formula (I) wherein Y stands for the radical (c)wherein R⁹ and R¹⁰ are as previously defined and wherein R⁸ stands forhydrogen, said compounds being represented by the formula (I-c-2), caneasily be obtained by desulfurating a compound of formula (I-c-1) in theusual manner, e.g., by treating the latter with Raney nickel or withdiluted nitric acid.

The compounds of formula (I) wherein Y represents the radical (c)wherein R⁹ and R¹⁰ are as previously described and wherein R⁸ is loweralkylthio or aryl-lower alkylthio, said compounds being represented bythe formula (I-c-3), can be prepared by subjecting the correspondingcompounds of formula (I-c-1) to a standard S-alkylation with a suitablereactive ester of the formula (XII), wherein R⁸ _(a) is lower alkyl oraryl-lower alkyl and wherein W is as previously defined.

In turn the compounds of formula (I-c-3) may be desulfurated yieldingthe compounds of formula (I-c-2).

The foregoing reactions are schematically illustrated as follows:##STR17##

The compounds of formula (I) wherein Y is the radical (d), wherein R¹¹represents XH, X being O or S, and wherein R¹² is hydrogen, lower alkylor aryl-lower alkyl, said R¹² being represented by R¹² _(a) and saidcompounds by the formula (I-d-1), can be prepared by cyclizing ahydrazinecarbothioamide or a hydrazinecarboxamide of formula (VIII-d-1)with an appropriate carboxylic acid of the formula ##STR18## or afunctional derivative thereof such as, for example, an acyl halide, anester, or preferably an imidamide of the formula ##STR19##

The reaction is conveniently carried out by stirring and heating thereactants together in an appropriate organic solvent, e.g., a loweralkanol such as, for example, 2-propanol, butanol and the like.

The compounds of formula (I-d-1) may alternatively be prepared by firstacylating (VIII-d-1) with an appropriate anhydride (XIII-b) or analkanoyl halide (XIII-c), derived from a carboxylic acid (XIII), toobtain an intermediate of formula (XIV), and, subsequently, cyclizingthe latter by stirring and heating (XIV) in an alcoholic alkalinemedium. ##STR20##

The intermediates of formula (VIII-d-1), used as starting materialsherein, may be prepared by the reaction of an alkali metalisothiocyanate, e.g., potassium isothiocyanate, with the correspondinghydrazine derivative of formula (VIII-b).

Still another method of preparing the compounds of formula (I-d-1) is byreacting a hydrazine hydrochloride of formula (VIII-b) with a compoundof formula (XIII-d) wherein X is O or S, in N,N-diethylethanamine,washing the reaction mixture with water, evaporating off the solvent andthereafter stirring and heating the residue in a mixture ofdichloromethane and ethanol in the presence of alkali. ##STR21##

The compounds of formula (I) wherein Y stands for the radical (d)wherein R¹² is R¹² _(a) and wherein R¹¹ is hydrogen, said compoundsbeing represented by the formula (I-d-2), can easily be prepared bydesulfurating a corresponding compound of formula (I-d-1), wherein R¹¹is SH, said compounds being represented by the formula (I-d-1-a)following the same procedure as for the desulfuration of (I-c-1) toprepare (I-c-2).

The compounds of formula (I) wherein Y stands for the radical (d)wherein R¹² is R¹² _(a) and wherein R¹¹ is lower alkylthio or aryl-loweralkylthio, said compounds being represented by the formula (I-d-3), canbe obtained by S-alkylating a compound of formula (I-d-1-a) with areactive ester of formula (XV-a), wherein W has the previously definedmeaning and wherein R¹¹ _(a) stands for lower alkyl or aryl-lower alkyl,following the same procedure as for the preparation of (I-c-3) startingfrom (I-c-1) and (XII). Following the same desulfurating procedure asdescribed hereinabove, the compounds of formula (I-c-3) may be convertedinto the compounds of formula (I-c-1).

The foregoing reactions are schematically illustrated as follows:##STR22##

The compounds of formula (I) wherein R¹² is XH, X being O or S, andwherein R¹¹ is hydrogen, lower alkyl or aryl-lower alkyl, said R¹¹ beingrepresented by R¹¹ _(b) and said compounds by the formula (I-d-4), maybe prepared by cyclizing an appropriate (aminocarbonyl)- or(aminothiocarbonyl)hydrazine of formula (VIII-d-2) with an appropriatecarboxylic acid (XIII-d) or a functional derivative thereof, e.g., anacyl halide, an ester or, preferably, an imidamide. Said reaction ispreferably carried out in the presence of an appropriate organicsolvent, e.g., a lower alkanol such as, for example, 2-propanol, butanoland the like. ##STR23##

The compounds of formula (I) wherein Y represents the radical (d)wherein R¹² is hydrogen and wherein R¹¹ has the meaning of R¹¹ _(b),said compounds being represented by the formula (I-d-5), may be preparedby desulfurizing a compound of formula (I-d-4) wherein X is S,(I-d-4-a), e.g., by treating the latter with Raney-nickel or withdiluted nitric acid.

The compounds of formula (I) wherein Y represents the radical (d)wherein R¹² is lower alkylthio or aryl-lower alkylthio and wherein R¹¹has the meaning of R¹¹ _(b) ; said compounds being represented by theformula (I-d-6), may be prepared by S-alkylating a compound of formula(I-d-4-a) with a reactive ester of formula (XV-b), wherein W is aspreviously described and wherein R¹² _(b) is lower alkyl or aryl-loweralkyl, following the previously described procedure for the preparationof (I-c-3) starting from (I-c-1) and (XII).

Following the desulfurating procedure described hereinabove, thecompounds of formula (I-d-6) may in turn be converted into the compoundsof formula (I-d-5).

The foregoing reactions are schematically illustrated as follows:##STR24##

The compounds of formula (I) wherein Y stands for a radical of formula(e) wherein R¹⁴ has the previously defined meaning and wherein R¹³stands for mercapto or hydroxy, said R¹³ being represented by XH,wherein X is O or S and said compounds by the formula (I-e-1), can bederived from an intermediate of formula (VIII-e) by cyclizing the latterwith an appropriate imidamide of formula (XVI) or an acid addition saltthereof. ##STR25##

The cyclization may be carried out according to methodologies known inthe art, for example, by mixing and melting the reactants together, ifdesired, in the presence of an appropriate reaction-inert organicsolvent having a relatively high boiling point such as, for example,1,1'-oxybis(2-methoxyethane).

The compounds of formula (I) wherein Y stands for the radical (e)wherein R¹⁴ is as previously defined and wherein R¹³ stands for loweralkylthio or aryl-lower alkylthio, said R¹³ being represented by SR¹³_(a), wherein R¹³ _(a) is lower alkyl or aryl-lower alkyl, saidcompounds being represented by the formula (I-e-3), can be prepared byS-alkylating a compound of formula (I-e-1) wherein R¹³ is --SH,(I-e-1-a), with a reactive ester of formula (XVII), wherein W has thepreviously defined meaning, following art-known procedures.

The compounds of formula (I) wherein Y stands for the radical (e)wherein R¹⁴ is as previously defined and wherein R¹³ stands forhydrogen, said compounds being represented by the formula (I-e-2), canbe prepared by desulfurizing a corresponding compound of formula(I-e-1-a) or a compound of formula (I-e-3), following standarddesulfuration reactions as previously described herein.

The foregoing reactions are schematically illustrated as follows:##STR26##

The compounds of formula (I) wherein Y represents a radical (f) whereinR¹⁵ and R¹⁶ have the previously defined meaning, said compounds beingrepresented by the formula (I-f), can be derived from an appropriatecompound of formula (I-e-1), wherein R¹³ stands for OH, (I-e-1-b), byN-alkylating the latter with an appropriate reactive ester of formula(XVIII), wherein W and R¹⁵ have the previously defined meanings.##STR27##

Said N-alkylation may be carried out in the usual manner, e.g., bystirring and heating the reactants together in an appropriate organicsolvent such as, for example, dimethylsulfoxide and the like, in thepresence of an appropriate base such as, for example, an alkali metalhydride or carbonate.

The compounds of formula (I) wherein Y stands for the radical (g)wherein R¹⁷ is as previously defined, but other than mercapto, saidcompounds being represented by the formula (I-g-1) and said R¹⁷ by R¹⁷_(a), can generally be derived from an intermediate of formula (VIII-a)by cyclizing the latter with an azide, preferably an alkali metal azide,e.g., sodium azide, and an appropriate 1,1',1"-tri(loweralkyloxy)-alkane of formula (XIX) in an appropriate acidic medium, e.g.,acetic acid, preferably under heating. ##STR28##

The compounds of formula (I), wherein Y stands for the radical (g)wherein R¹⁷ stands for mercapto, said compounds being represented by theformula (I-g-2) can be obtained by cyclizing an isothiocyanate offormula (VIII-c) with an appropriate azide, preferably sodium azide, inan appropriate organic solvent, e.g., a lower alkanol such as methanol,ethanol, 2-propanol and the like, in the presence of alkali. ##STR29##

Said cyclization reaction may also be carried out by stirring (VIII-c)with an azide in the presence of an appropriate quaternary ammoniumsalt, preferably N,N,N-triethylbenzenemethanaminium chloride, in asuitable solvent system such as, for example, water, preferably inadmixture with an appropriate organic solvent such as, for example,1,4-dioxane, to better solubilize the reactants.

The compounds of formula (I-g) wherein R¹⁷ is hydrogen (I-g-3), may beprepared by desulfurating a compound of formula (I-g-2) following artknown procedures. ##STR30##

The imidazole- and triazole-derivatives of formula (I), obtained in baseform in the foregoing preparations, may be converted to theirtherapeutically useful acid addition salts by reaction with anappropriate acid, as, for example, an inorganic acid such as hydrohalicacid, i.e., hydrochloric, hydrobromic or hydroiodic acid; sulfuric,nitric or thiocyanic acid; a phosphoric acid; an organic acid such asacetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, 1,4-butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxy-1,4-butanedioic,2,3-dihydroxy-1,4-butanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,benzoic, 3-phenyl-2-propenoic, α-hydroxybenzeneacetic, methanesulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, 4-methylbenzenesulfonic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic, 2-phenoxybenzoic or2-acetyloxybenzoic acid. The salts are in turn converted to thecorresponding free bases in the usual manner, e.g., by reaction withalkali such as sodium or potassium hydroxide.

A number of the intermediates and starting materials used in theforegoing preparations are known compounds, others may be preparedaccording to art-known methodologies of preparing similar compounds andsome of them are novel and consequently their preparation will bedescribed hereafter.

The intermediates of formula (III), wherein Y' has the previouslydefined meaning, can generally be prepared from the correspondingmethoxy-substituted compounds of formula (XX) by converting the methoxygroup of the latter into a hydroxy group by acid hydrolysis using astrong non-oxidizing mineral acid such as, for example, hydrobromic acidin glacial acetic acid. ##STR31##

The intermediates of formula (XX), used as starting materials herein,can be obtained by cyclizing a N,N-bis(2-haloethyl)-4-methoxybenzenamineof formula (XXI), with an appropriate benzenamine of formula (XXII),wherein Y' has the previously defined meaning, following the sameprocedure as described for the preparation of (I) starting from (IV) and(V). ##STR32##

The preparation of the compounds of formula (XXI) is described inJ.Chem.Soc., 1949, 183-191.

The intermediates of formula (XX) can alternatively be prepared bycyclizing an appropriate intermediate of formula (XXIII), wherein A isan amine group or a derivative thereof, with an appropriate cyclizingagent and, if desired, introducing appropriate substituents into thethus obtained heterocyclic compounds, following the previously describedmethods for the preparation of compounds (I) starting from (VIII).##STR33##

The intermediates of formula (XXIII) wherein A stands for an aminogroup, (XXIII-a), can be prepared by N-alkylating a compound of formula(XXIV) with an appropriate chloro-nitrobenzene (XXV), following standardN-alkylating procedures, and subsequently reducing the thus obtainednitro-compound (XXVI), e.g., by catalytic hydrogenation in a relativelypolar solvent, such as, for example, methanol, in the presence of anappropriate catalyst, e.g., palladium on charcoal. ##STR34##

The intermediates of formula (XXIII), wherein A represents anisothiocyanate group, (XXIII-b), can be derived from an appropriatecompound of formula (XXIII-a), by treating the latter with carbondisulfide in the presence of dicyclohexylcarbodiimide, preferably in thepresence of an appropriate organic solvent such as, for example,pyridine. ##STR35##

The intermediates of formula (XXIII), wherein A stands for ahydrazinecarbothioamide group, (XXIII-c-1), can be derived from acompound of formula (XXIII-b), by stirring and heating the latter withhydrazine hydrate in the presence of an appropriate solvent such as, forexample, 1,4-dioxane and the like. ##STR36##

The intermediates of formula (XXIII), wherein A stands for ahydrazinecarbonamide group, (XXIII-c-2), can be derived from a compoundof formula (XXIII-a), by stirring and heating the latter withphenylcarbonohalogenidate in an appropriate solvent, e.g.,dichloromethane, in the presence of an appropriate base such as, forexample, pyridine and the like, and subsequently reacting the thusobtained (XXIII-d) with hydrazine hydrate in the presence of anappropriate solvent, e.g., 1,4-dioxane and the like. ##STR37##

The intermediates of formula (IV) can be prepared by O-alkylating a4-amino-phenol of formula (XXVI) with a reactive ester of formula (II),following the same procedure as previously described herein for thepreparation of (I'), and subsequently reacting the thus obtainedcompounds of formula (XXVII) with an appropriate dihaloethane, followingthe method described in J.Chem.Soc., 1949, 183-191. ##STR38##

The intermediates of formula (V) and the starting materials of formula(XXII) can generally be prepared by reducing a corresponding nitrocompound of formula (XXVIII), respectively (XXVIII-a), e.g., bycatalytic hydrogenation in a relatively polar solvent such as, forexample, an alkanol, in the presence of an appropriate catalyst, e.g.,platinum on charcoal. ##STR39##

The starting materials of formula (XXVIII), respectively (XXVIII-a), canbe prepared starting from appropriate precursors, following art-knownprocedures as previously described herein for the preparation ofcompounds of formula (I) starting from (VIII) and an appropriatecyclizing agent.

The intermediates of formula (VI) can be obtained by O-alkylating anappropriate compound of formula (XXIX) with a reactive ester of formula(II), following standard O-alkylation procedures. ##STR40##

Starting materials of formula (II) wherein O stands for CH and methodsof preparing the same are described in Belg. Pat. No. 837,831. Ingeneral the reactive esters of formula (II) can be prepared along thefollowing sequence of reactions.

An appropriate I-Ar-2-bromoethanone of formula (XXX) is subjected to aketalization reaction with 1,2,3-propanetriol following methodologiesanalogous to those described in Synthesis, 1974, (I), 23.

In a preferred manner of carrying out the reaction both reactants arerefluxed together for several hours with azeotropic water removal in anappropriate organic solvent, preferably in the presence of a simplealcohol, such as, for example, ethanol, propanol, butanol, pentanol andthe like, and in the presence of an appropriate strong acid such as4-methylbenzenesulfonic acid. Suitable organic solvents are, forexample, aromatic hydrocarbons, such as benzene, methylbenzene,dimethylbenzene and the like and saturated hydrocarbons, such ascyclohexane.

The thus obtained dioxolane (XXXI) is then reacted with benzoyl chlorideto obtain a benzoate of the formula (XXXII) and the latter issubsequently reacted with 1H-imidazole or 1H-1,2,4-triazole. Saidreaction is preferably carried out by stirring and heating the reactantstogether in a suitable organic solvent, e.g., N,N-dimethylformamide, inthe presence of an appropriate strong metal base, e.g., sodiummethanolate, to obtain an intermediate of the formula (XXXIII). Thedesired reactive esters of formula (II) are then conveniently preparedby first hydrolyzing (XXXIV) in alkaline medium and thereafterconverting the hydroxy group of the thus obtained (XXXV) into a reactiveester thereof according to methodologies generally known in the art. Forexample, methanesulfonates and 4-methylbenzenesulfonates areconveniently prepared by the reaction of the alcohol withmethanesulfonyl chloride or 4-methylbenzenesulfonyl chloride and halidesmay be prepared by the reaction of the alcohol with an appropriatehalogenating agent such as, for example, thionyl chloride, phosphorpentachloride, phosphor pentabromide, phosphoryl chloride and the like.When the reactive ester is an iodide, it is preferably prepared from thecorresponding chloride or bromide by the replacement of that halogenwith iodine.

The foregoing reactions may be illustrated as follows: ##STR41##

From formula (I) it is evident that the compounds of this invention haveat least two asymmetric carbon atoms in their structures, namely thoselocated in the 2- and 4-position of the dioxolane nucleus, andconsequently they can exist under different stereochemically isomericforms. The stereochemically isomeric forms of (I) and thepharmaceutically acceptable acid addition salts thereof are intended tobe within the scope of this invention.

The diastereomeric racemates of (I), denoted as cis and trans formsrespectively, according to the rules described in C.A., 76, Index Guide,Section IV, p. 85 (1972), may be obtained separately by conventionalmethods. Appropriate methods which may advantageously be employedtherefore include, for example, selective crystallization andchromatographic separation, e.g., column-chromatography.

Since the stereochemical configuration is already fixed in a number ofintermediate compounds, e.g., in intermediates of the formulas (II),(IV), (VI) and (VIII) it is also possible to separate cis and transforms at this or even an earlier stage, whereupon the correspondingforms of (I) may be derived therefrom in the previously indicatedmanner. The separation of cis and trans forms of such intermediates maybe performed by conventional methods as described hereabove for theseparation of cis and trans forms of the compounds (I).

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

The compounds of formula (I) and the pharmaceutically acceptable acidaddition salts thereof are useful agents in combatting fungi andbacteria. For example, said compounds and acid addition salts thereofwere found to be highly active against a wide variety of fungi such as,for example, Microsporum canis, Ctenomyces mentagrophytes, Trichophytonrubrum, Phialophora verrucosa, Cryptococcus neoformans, Candidatropicalis, Candida albicans, Mucor species, Aspergillus fumigatus,Sporotricum schenckii and Saprolegnia species, and against bacteria suchas, for example, Erysipelotrix insidiosa, Staphylococci such asStaphylococcus hemolyticus and Streptococci such as Streptococcuspyogenes. In view of their potent, local as well as systemic,antimicrobial activity the compounds of this invention constitute usefultools for the destruction or prevention of the growth of fungi andbacteria and more particularly they can effectively be used in thetreatment of subjects suffering from such microorganisms.

The strong antimicrobial activity of the compounds (I) is clearlyevidenced by the data obtained in the following experiments, which dataare only given to illustrate the useful antimicrobial properties of allthe compounds (I) and not to limit the invention either with respect tothe scope of susceptible microorganisms nor with respect to the scope offormula (I).

EXPERIMENT A Activity of compounds (I) against vaginal candidosis inrats

Female Wistar rats of ±100 g body weight are used. They areovariectomized and hysterectomized and after three weeks of recovery,100 μg of oestradiol undecylate in sesame oil is given subcutaneouslyonce a week for 3 consecutive weeks. The thus induced pseudo-oestrus iscontrolled by microscopic examination of vaginal smears. Food and waterare left available ad libitum. The rats are infected intravaginally with8.10⁵ cells of Candida albicans, grown on Sabouraud broth for 48 hoursat 37° C. and diluted with saline. The date of infection varies from day+25 to day +32 after surgical intervention, depending on the appearanceof signs of induced pseudo-oestrus.

The drugs under investigation are administered orally once a day for twodays starting from the day of infection. For each experiment there areplacebo treated controls. The results are assessed by taking vaginalsmears with sterile swabs on several days after the infection. The swabsare put into Sabouraud broth in petri-dishes and incubated for 48 hoursat 37° C. If no growth of Candida albicans occurs, i.e., wher theanimals are negative at the end of the experiment, this is due to drugadministration because it never happens in placebo-treated controls.

The table below gives the lowest oral dose of the drug underinvestigation which is found active at the 14th day after infection.

EXPERIMENT B Activity of compounds (I) against crop candidosis inturkeys

Turkeys of 14 days old are infected in the crop with 4.10⁶ Candidaalbicans cells, grown on Sabouraud broth for 48 hours at 37° C. anddiluted with saline. The volume of the inoculum is 1 ml. The drugs underinvestigation are premixed in 500 mg of lacton and thereafter admixed in1000 g of meal without any additives. The concentration of the drugunder investigation in the meal is expressed in mg/kg.

The animals are given the medicated feed for 13 consecutive daysstarting on the day of infection. At the end of the experiment allanimals are sacrified. At autopsy the crops are removed, emptied andgrinded in an ultra-turrax mixer in 15 ml of sterile saline. Colonycounting is done on Sabouraud agar and the results given in the tablerepresent the ED₅₀, i.e., the dose of the drug whereby the crops of 50%of the animals are completely negative for Candida albicans.

The compounds listed in the table are intended to illustrate and not tolimit the scope of the present invention.

    ______________________________________                                         ##STR42##                                                                                                        Crop                                                       Vaginal candidosis                                                                   candidosis in                                                          in rats: lowest                                                                      turkeys: ED.sub.50                                                     effective dose in                                                                    in mg/kg                                              Y Q              mg/kg orally                                                                         in feed.                                              ______________________________________                                         ##STR43##   CH     2.5           --                                           ##STR44##   N      2.5           --                                           ##STR45##   CH     1.25          --                                           ##STR46##   N      1.25          16                                           ##STR47##   CH     0.63          16                                           ##STR48##   N      0.63          --                                           ##STR49##   CH     2.5           --                                           ##STR50##   N      1.25          31                                           ##STR51##   CH     2.5           --                                           ##STR52##   N      ≦0.63  --                                           ##STR53##   N      2.5           --                                           ##STR54##   N      2.5           --                                           ##STR55##   N      0.63          --                                           ##STR56##   CH     --            31                                           ##STR57##   CH     0.63          16                                           ##STR58##   N      ≦0.63  16                                           ##STR59##   N      <2.5          --                                           ##STR60##   N      ≧0.63  --                                           ##STR61##   CH     1.0           16                                           ##STR62##   CH     1.25          31                                           ##STR63##   CH     0.63          --                                           ##STR64##   N      <0.63         --                                           ##STR65##   N      0.5           --                                           ##STR66##   N      ≧0.16  --                                           ##STR67##   CH     1.25          --                                          ______________________________________                                    

In view of their antifungal and antibacterial properties this inventionprovides valuable compositions comprising the subject compounds offormula (I) or acid addition salts thereof as the active ingredient in asolvent or a solid, semi-solid or liquid diluent or carrier, and, inaddition, it provides an effective method of combatting fungal orbacterial growth by use of an effective antifungal or antibacterialamount of such compounds (I) or salts thereof. Antifungal andantibacterial compositions comprising an effective amount of an activecompound (I), either alone or in combination with other activetherapeutic ingredients, in admixture with suitable carriers may bereadily prepared according to conventional pharmaceutical techniques forthe usual routes of administration.

Preferred compositions are in dosage unit form, comprising per dosageunit an effective quantity of the active ingredient in admixture withsuitable carriers. Although the amount of the active ingredient per unitdosage may vary within rather wide limits, dosage units comprising fromabout 50 to about 500 mg and more particularly from about 100 to about250 mg of the active ingredient are preferred.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Unless otherwise stated all parts therein are by weight.

(A) Preparation of intermediates:

EXAMPLE I

A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazinedihydrochloride, 7.9 parts of 1-chloro-4-nitrobenzene, 10 parts ofpotassium carbonate and 90 parts of N,N-dimethylformamide is stirred andrefluxed overnight. The reaction mixture is diluted with water and theproduct is extracted twice with trichloromethane. The combined extractsare dried, filtered and evaporated. The residue is triturated in4-methyl-2-pentanone. The product is filtered off and crystallized from1,4-dioxane, yielding 10.5 parts (67%) of1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; mp. 195.1° C.

A mixture of 12 parts of1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanoland 225 parts of tetrahydrofuran is hydrogenated at normal pressure andat room temperature with 2 parts of palladium-on-charcoal catalyst 10%.After the calculated amount of hydrogen is taken up, the catalyst isfiltered off and washed with N,N-dimethylacetamide. The filtrate ispoured onto water. The precipitated product is filtered off andcrystallized from 1-butanol, yielding 8 parts (74%) of4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 191.8° C.

EXAMPLE II

To a stirred and cooled (ice-bath) mixture of 5 parts ofN,N'-methanetetraylbis[cyclohexanamine], 25.2 parts of carbon disulfideand 40 parts of pyridine are added 6 parts of4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and the whole isstirred first for 1 hour in an ice-bath and further for 2 hours at roomtemperature. 35 Parts of 2,2'-oxybispropane are added and the whole isstirred for 30 minutes. The precipitated product is filtered off andcrystallized from 4-methyl-2-pentanone. The product is filtered offagain and recrystallized from 1,4-dioxane, yielding 2.45 parts of1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine; mp. 180.6° C.

A mixture of 47.8 parts of1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 100 parts ofhydrazine hydrate and 400 parts of 1,4-dioxane is stirred and refluxedfor 1 hour. The reaction mixture is cooled and poured onto water. Theprecipitated product is filtered off, washed with water and withmethanol and dried, yielding 46 parts (89%) ofN-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide.

EXAMPLE III

A mixture of 23 parts ofN-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide,23 parts of methanimidamide acetate and 80 parts of 1-butanol is stirredand refluxed for 1 hour. The reaction mixture is cooled and poured ontowater. 2,2'-oxybispropane is added. The precipitated product is filteredoff, washed with water and with methanol and crystallized from1-butanol, yielding 17.7 parts of4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-4H-1,2,4-triazole-3-thiol;mp. 231.9° C.

Following the same procedure and using an equivalent amount ofethanimidamide hydrochloride in place of the methanimidamide acetateused therein, there is obtained4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-5-methyl-4H-1,2,4-triazole-3-thiol;mp. 260.3° C.

EXAMPLE IV

A mixture of 9 parts of4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-4H-1,2,4-triazole-3-thiol,2 parts of sodium hydroxide and 160 parts of methanol is stirred andwarmed till all solid enters solution. Then there are added 3.3 parts ofdimethyl sulfate and stirring is continued for 3 hours at roomtemperature. The reaction mixture is poured onto water. The precipitatedproduct is filtered off and crystallized from 1-butanol, yielding 5.3parts of1-(4-methoxyphenyl)-4-{4-[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine;mp. 180° C.

In a similar manner there is prepared:

1-(4-methoxyphenyl)-4-{4-[3-methyl-5-(methylthio)-4H-1,2,4-traizol-4-yl]phenyl}piperazinedihydrochloride; mp. 210° C.

EXAMPLE V

A mixture of 50 parts of 2-(4-nitrophenyl)hydrazinecarbothioamide and270 parts of methylbenzene is distilled azeotropically to dry. Thenthere are added 26 parts of acetic acid anhydride and the whole isstirred and refluxed for 3 hours. The reaction mixture is cooled. Theprecipitated product is filtered off, washed with 2-propanol andcrystallized from ethanol. It is filtered off again and dried at 100°C., yielding 31.5 parts of acetic acid,2-(aminothioxomethyl)-1-(4-nitrophenyl)hydrazide; mp. 241.5° C.

Following the same acetylation-procedure and using equivalent amounts ofthe appropriate starting materials there are also prepared:

butanoic acid, 2-(aminothioxomethyl)-1-(4-nitrophenyl)hydrazidemonohydrate; mp. 197.2° C.; and

propanoic acid, 2-(aminothioxomethyl)-1-(4-nitrophenyl)hydrazide; mp.216.1° C.

EXAMPLE VI

40 Parts of acetic acid,2-(aminothioxomethyl)-1-(4-nitrophenyl)hydrazide are dissolved in amixture of 10 parts of sodium hydroxide and 400 parts of water and thesolution is stirred for 30 minutes at room temperature. The reactionmixture is acidified with concentrated hydrochloric acid. Theprecipitated product is filtered off, washed with water and with2-propanol and crystallized from 1,4-dioxane, yielding 22.4 parts of5-methyl-1-(4-nitrophenyl)-1H-1,2,4-traizole-3-thiol; mp. 202.1° C.

In a similar manner there are also prepared:

1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole-3-thiol; mp. 190.7° C.; and

5-ethyl-1-(4-nitrophenyl)-1H-1,2,4-triazole-3-thiol; mp. 206.1° C.

EXAMPLE VII

To 80 parts of methanol are added 4.7 parts of5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole-3-thiol and 1.2 parts ofsodium hydroxide and the whole is stirred till all solid enterssolution. Then there are added 2.66 parts of dimethyl sulfate andstirring is continued for 1 hour at room temperature. 100 Parts of waterare added. The precipitated product is filtered off, washed with water,dried, and crystallized from 2,2'-oxybispropane, yielding 3.3 parts(66%) of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole;mp. 121°-125° C.

Following the same S-methylation procedure and using equivalent amountsof the appropriate starting materials there are also prepared:

5-ethyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole; mp. 77.8°C.; and

3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole; mp. 140° C.

EXAMPLE VIII

A mixture of 2.5 parts of5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 120parts of methanol is hydrogenated at normal pressure and at roomtemperature with 2 parts of platinum-on-characoal catalyst 10%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated. The residue is crystallized from amixture of 4-methyl-2-pentanone and petroleumether. The product isfiltered off and dried, yielding 1.5 parts (68%)4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp.130°-136° C.

Following the same hydrogenation-procedure there is also prepared:

4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine as a residue.

EXAMPLE IX

A mixture of 41 parts of5-ethyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 80 partsof methanol is hydrogenated at normal pressure and at room temperaturewith 1 part of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The residue is crystallized from1,1'-oxybisbutane. The product is filtered off and dried, yielding 33parts (91%) of4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 131.7°C.

In a similar manner there is also prepared:

4-(2-methyl-1H-imidazol-1-yl)benzenamine; mp. 105° C.

EXAMPLE X

A mixture of 20 parts of4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine, 15 partsof Raney-nickel catalyst and 400 parts of methanol is stirred andrefluxed for 2 hours. The Raney-nickel is filtered off and another 15parts of the catalyst are added. Stirring at reflux is continued for 4hours. The reaction mixture is filtered, washed on the filter withmethanol and the filtrate is evaporated. The residue is crystallizedfrom a mixture of 4-methyl-2-pentanone, 2,2'-oxybispropane andpetroleumether. The product is filtered off and dried, yielding 7.6parts (47%) of 4-(5-methyl-1H-1,2,4-triazol-1-yl)benzenamine; mp. 145°C.

EXAMPLE XI

A mixure of 35 parts of1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole-3-thiol, 83 parts ofconcentrated nitric acid solution and 150 parts of water is stirred andwarmed to 60° C. While stirring, the mixture is allowed to cool to roomtemperature and the whole is further stirred overnight at roomtemperature. The precipitated product is filtered off, washed with waterand added to a hot solution of 20 parts of potassium carbonate in 200parts of water at 100° C. The reaction mixture is allowed to cool toroom temperature while stirring. The precipitated product is filteredoff, dried and crystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The product is filtered off and recrystallized from4-methyl-2-pentanone, yielding 19.8 parts of3,3'-dithiobis[1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole]; mp. 171.5°C.

20 Parts of 3,3'-dithiobis[1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole]are dissolved in 100 parts of acetic acid while stirring and warming.Then there are added dropwise 55 parts of hydrogen peroxide solution30%: reflux temperature is reached. Upon completion, stirring at refluxis continued for 1 hour. The reaction mixture is cooled and poured ontoa mixture of crushed ice and a sodium hydroxide solution 50%. Theprecipitated product is filtered off and dissolved in dichloromethane.The solution is washed with a sodium sulfite solution, dried, filteredand evaporated. The residue is purified by column-chromatography oversilica gel using trichloromethane as eluent. The pure fractions arecollected and the eluent is evaporated. The residue is converted intothe hydrochloride salt in 2-propanol. The salt is filtered off andcrystallized from ethanol, yielding 3.9 parts (19%) of1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole monohydrochloride; mp.178.7° C.

A mixture of 38.3 parts of 1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazolemonohydrochloride and 400 parts of methanol is hydrogenated at normalpressure and at room temperature with 3 parts of palladium-on-charcoalcatalyst 10%. After the calculated amount of hydrogen is taken up, thecatalyst is filtered off and the filtrate is evaporated. The residue isdissolved in water and neutralized with sodium hydrogen carbonate. Theproduct is extracted with dichloromethane. The extract is washed withwater, dried, filtered and evaporated. The residue is converted into thehydrochloride salt in 2-propanol. The salt is filtered off and dried,yielding 35 parts (91%) of 4-(5-propyl-1H-1,2,4-triazol-1-yl)benzenaminedihydrochloride.

EXAMPLE XII

A mixture of 4 parts of N-(4-nitrophenyl)hydrazinecarboxamide, 5 partsof ethanimidamide hydrochloride and 5 parts of sodium acetate is stirredand heated for 4 hours at 140° C. The reaction mixture is cooled, wateris added and the whole is stirred till the product is crystallized. Itis filtered off and recrystallized from 2-propanol, yielding 1.5 parts(34%) of 2,4-dihydro-5-methyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one;mp. 226.1° C.

To a stirred solution of 13.5 parts of2,4-dihydro-5-methyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one in 100parts of dimethyl sulfoxide are added 2 parts of sodium hydridedispersion 78% and the whole is stirred till foaming has ceased. Thenthere are added dropwise 8.1 parts of dimethyl sulfate. Upon completion,stirring is continued for 3 hours at room temperature. The reactionmixture is poured onto water and the product is extracted three timeswith trichioromethane. The combined extracts are washed with water,dried, filtered and evaporated. The residue is crystallized from amixture of 2-propanol and 2,2'-oxybispropane. The product is filteredoff and recrystallized from 4-methyl-2-pentanone, yielding 6.3 parts of2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one; mp.153.2° C.

A mixture of 9 parts of2,4-dihydro-2,5-dimethyl-4-(4-nitrophenyl)-3H-1,2,4-triazol-3-one and200 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 3 parts of Raney-nickel catalyst. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The residue is triturated in 2,2'-oxybispropane.The product is filtered off and dried, yielding 7.5 parts (95%) of4-(4-aminophenyl)-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one; mp.160° C.

EXAMPLE XIII

A mixture of 53 parts ofN-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide, 53parts of ethanimidamide hydrochloride and 135 parts ofN,N-dimethylformamide is stirred and heated for 3 hours at 130° C. Thereaction mixture is cooled and poured onto water. The precipitatedproduct is filtered off, washed with water and with methanol, andcrystallized from N,N-dimethylformamide. The product is filtered off andrecrystallized from 1,4-dioxane, yielding 19.5 parts of2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-5-methyl-3H-1,2,4-triazol-3-one;298.4° C.

EXAMPLE XIV

19.2 Parts of2,4-dihydro-4-{4-[4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-oneare dissolved in 450 parts of dimethyl sulfoxide at about 100° C. Thenthere are added 3.1 parts of sodium hydride dispersion 50% and the wholeis stirred till a temperature of about 50° C. is reached. 8.2 Parts ofdimethyl sulfate are added and stirring is continued overnight at roomtemperature. The reaction mixture is poured onto water and the productis extracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (98:2 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from 1-butanol, yielding 5.8 parts of2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2-methyl-3H-1,2,4-triazol-3-one;mp. 245.7° C.

EXAMPLE XV

10 Parts of2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-oneare dissolved in 300 parts of dimethyl sulfoxide at 100° C. Then thereare added 1.6 parts of sodium hydride dispersion 50% and stirring iscontinued while the mixture is allowed to cool to about 50° C. 3.9 Partsof 1-bromopropane are added and the whole is stirred overnight at roomtemperature. The reaction mixture is poured onto water and the productis extracted with trichloromethane. The extract is washed with water,dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue istriturated in 2-propanol. The product is filtered off and dried;yielding 7.5 parts (65%) of2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2-propyl-3H-1,2,4-triazol-3-one.

Following the same N-alkylation-procedure and using equivalent amountsof the appropriate starting materials there are prepared:

2-ethyl-2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl}-5-methyl-3H-1,2,4-triazol-3-one;mp. 179.8° C.

2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-5-methyl-2-propyl-3H-1,2,4-triazol-3-one;mp. 144.5° C.; and

2-ethyl-2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl}-3H-1,2,4-triazol-3-one; mp. 210.2° C.

EXAMPLE XVI

A mixture of 12.5 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine,8 parts of 4-(1H-pyrazol-1-yl)benzenamine, 2 parts of potassium iodide,80 parts of 2-propanone and 100 parts of water is stirred and refluxedfor 24 hours. The reaction mixture is cooled. The precipitated productis filtered off (the filtrate is set aside), washed with water and with2-propanone, yielding a first crude fraction of 6 parts. The filtrate(see above) is neutralized with a sodium hydrogen carbonate solution andextracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is triturated in 2-propanol. The product isfiltered off and washed with methanol, yielding a second crude fractionof 2 parts. The combined crude crops (resp. 6 and 2 parts) arecrystallized from 1-butanol, yielding 7.1 parts of1-(4-methoxyphenyl)-4-[4-(1H-pyrazol-1-yl)phenyl]piperazine; mp. 207.7°C.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

1-[4-(1H-imidazol-1-yl)phenyl]-4-(4-methoxyphenyl)piperazine; mp.255°-256° C.;

1-(4-methoxyphenyl)-4-[4-(1H-1,2,4-triazol-1-yl)phenyl]piperazine; mp.230.3° C.;

1-(4-methoxyphenyl)-4-{4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 186.5° C.;

1-(4-methoxyphenyl)-4-{4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 153.3° C.;

1-(4-methoxyphenyl)-4-[4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 191.1° C.;

2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2,5-dimethyl-3H-1,2,4-triazol-3-one;mp. 196.7° C.;

1-(4-methoxyphenyl)-4-[4-(5-propyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 196.3° C.;

1-{4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}-4-(4-methoxyphenyl)piperazine;mp. 142.3° C.; and

1-(4-methoxyphenyl)-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]piperazine;mp. 178.5° C.

EXAMPLE XVII

A mixture of 6 parts of4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine, 3.6 parts of phenylcarbonochloridate, 75 parts of pyridine and 98 parts of dichloromethaneis stirred and warmed till all solid enters solution. Stirring iscontinued for 30 minutes at room temperature. The reaction mixture ispoured onto 500 parts of water and 210 parts of 2,2'-oxybispropane areadded. The whole is stirred for a while. The precipitated product isfiltered off and crystallized from 1-butanol, yielding 5.2 parts (61%)of phenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate; mp.204.5° C.

A mixture of 3.2 parts ofphenyl{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}carbamate, 50 partsof hydrazine hydrate and 100 parts of 1,4-dioxane is stirred andrefluxed for 3 hours. The reaction mixture is cooled and poured ontowater. The precipitated product is filtered off and crystallized fromN,N-dimethylformamide, yielding 1.7 parts (63%) ofN-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide; mp.+300° C.

A mixture of 3.4 parts ofN-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide, 3parts of methanimidamide acetate and 10 parts of dimethyl sulfoxide isstirred and heated for 2 hours at 100° C. The reaction mixture is cooledand poured onto a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The precipitated product is filtered off andcrystallized from N,N-dimethylformamide (activated charcoal), yielding 1part (28%) of2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one;mp. +300° C.

EXAMPLE XVIII

A mixture of 30 parts of4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine and 300 parts of ahydrobromic acid solution 48% in water is stirred and refluxed for 10days. The reaction mixture is evaporated and the residue is alkalizedwith sodium hydroxide. The mixture is filtered and the filtrate isacidified with acetic acid. The precipitated product is filtered off andcrystallized from 1,4-dioxane, yielding 12 parts (44%) of4-[4-(4-aminophenyl)-1-piperazinyl]phenol.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

4-{4-[4-(1H-pyrazol-1-yl)phenyl]-1-piperazinyl}phenol;

4-{4-[4-(1H-imidazol-1-yl)phenyl]-1-piperazinyl}phenol; mp.>260° C.

4-{4-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1-piperazinyl}phenol; mp. 276.6°C.

4-[4-{4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}-1-piperazinyl]phenol;mp. 225.5° C.

4-[4-{4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}-1-piperazinyl]phenol;mp. 255.8° C.

4-[4-{4-[3-methyl-5-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}-1-piperazinyl]phenol;

4-{4-[4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]-1-piperazinyl}phenol;mp. 281.1° C.

4-[4-{4-[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}-1-piperazinyl]phenol;

2,4-dihydro-4-{4-[4-(4-hyroxyphenyl)-1-piperazinyl]phenyl}-2,5-dimethyl-3H-1,2,4-triazol-3-one;mp. +260° C.;

2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl}-2-propyl-3H-1,2,4-triazol-3-one;

4-{4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-1-piperazinyl}phenol; mp.+300° C.;

4-[4-{4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}-1-piperazinyl]phenol;mp. 232.6° C.;

2-ethyl-2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl}-5-methyl-3H-1,2,4-triazol-3-one;mp. 287.8° C.;

2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl}-5-methyl-2-propyl-3H-1,2,4-triazol-3-one;mp. 258.2° C.;

2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl}-2-methyl-3H-1,2,4-triazol-3-one;

2-ethyl-2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one;mp. 217° C.; and

4-{4-[4-(5-propyl-1H-1,2,4-triazol -1-yl)phenyl]-1-piperazinyl}phenol;mp. 225.6° C.

B. Preparation of final compounds

EXAMPLE XIX

To a stirred solution of 3 parts of4-[4-(4-aminophenyl)-1-piperazinyl]phenol in 50 parts ofdimethylsulfoxide are added 0.5 parts of a sodium hydride dispersion50%. The whole is stirred at 50° C. till foaming has ceased. Then thereare added 4.1 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-2-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonateand stirring is continued for 2 hours at 70° C. The reaction mixture iscooled and poured onto water. The product is extracted withdichloromethane. The extract is washed with a diluted sodium hydroxidesolution, dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 2-propanol. The product is filtered off and dried,yielding 1.3 parts (22%) ofcis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]benzenamime;mp. 174.4° C.

EXAMPLE XX

To a solution of 3.2 parts of4-{4-[4-(1H-pyrazol-1-yl)phenyl]-1-piperazinyl}phenol in 100 parts ofdimethyl sulfoxide are added 0.32 parts of a sodium hydride dispersion78% and the whole is stirred at 50° C. till foaming has ceased. Then 4.1parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate are added and stirring is continued for 3 hours at 100°C. The reaction mixture is cooled, poured onto water and the product isextracted with dichloromethane. The extract is washed with dilutedsodium hydroxide solution dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue ispurified again by column-chromatography over silica gel using a mixtureof methylbenzene and ethanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from methylbenzene, yielding 2.2 parts (34%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(1H-pyrazol-1-yl)phenyl]piperazine;mp. 195.1° C.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(1H-imidazol-1-yl)phenyl]piperazine;mp. 166.7° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 175.3° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-{4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 178.3° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-{4-[3-methyl-5-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine;mp. 127.8° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 188.9° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-{4-[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine;mp. 176.4;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-one;mp. 149.3° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one;mp. 185.7° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 154.1° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]piperazine;mp. 180.1° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 212.8° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 204.7° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-5-methyl-2-propyl-3H-1,2,4-triazol-3-onemonohydrate; mp. 153.9° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-{4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 136.3° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(5-propyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 150.4° C.; and

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-onemonohydrate; mp. 135.5° C.

EXAMPLE XXI

A mixture of 2 parts of sodium azide, 5.8 parts ofcis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]benzenamine,4 parts of 1,1',1"-[methylidynetris(oxy)]trisethane and 50 parts ofacetic acid is stirred and heated overnight at 70° C. The reactionmixture is cooled and neutralized with a potassium carbonate solution.The product is extracted with dichloromethane. The extract is dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 1-butanol. The product is filtered off and dried,yielding 3.8 parts (60%) of cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-tetrazol-1-yl)phenyl]piperazine;mp. 201.3° C.

EXAMPLE XXII

To a stirred solution of 8 parts of4-[4-(4-aminophenyl)-1-piperazinyl]phenol in 100 parts of dimethylsulfoxide are added 1.5 parts of sodium hydride dispersion 50% andstirring is continued till foaming has ceased. Then there are added 12.3parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonateand the whole is stirred and heated for 4 hours at 50° C. The reactionmixture is cooled and poured onto water. The product is extracted threetimes with dichloromethane. The combined extracts are washed with adiluted sodium hydroxide solution and treated with activated charcoal.The latter is filtered off and the filtrate is evaporated. The residueis purified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 1-butanol, yielding 5.1 parts of cis-1-[4-{4-[2-(2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]benzenamine;mp. 186.8° C.

EXAMPLE XXIII

To a stirred solution of 3 parts of4-{4-[4-(1H-1,2,4-triazol-1-yl)phenyl]-1-piperazinyl}phenol in 100 partsof dimethyl sulfoxide are added 0.3 parts of sodium hydride dispersion78% and the whole is stirred at 50° C. till foaming has ceased. Thenthere are added 3.7 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methane-sulfonateand stirring is continued for 3 hours at 100° C. The reaction mixture iscooled and poured onto water. The product is extracted three times withdichloromethane. The combined extracts are washed with a diluted sodiumhydroxide solution, dried, filtered and evaporated. The residue iscrystallized from 1-butanol. The product is filtered off and dried,yielding 4.3 parts (75%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-1,2,4-triazol-1-yl)phenyl]piperazine; mp. 219.6° C.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are also prepared:

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-pyrazol-1-yl)phenyl]piperazine;mp. 188.3° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-imidazol-1-yl)phenyl]piperazine;mp. 194.3° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 166.5° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-{4-[3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 153.9° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-{4-[5-methyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]phenyl}piperazine;mp. 164.1° C.

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl-methoxy]phenyl}-1-piperazinyl]phenyl}-3-(methylthio)-4H-1,2,4-triazole;mp. 147°-152.6° C.

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-{4-[3-methyl-5-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine;mp. 118.3° C.

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2,5-dimethyl-3H-1,2,4-triazol-3-onemonohydrate; mp. 161.9° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one;mp. 167.3° C.;

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(2-methyl-1H-imidazol-1-yl)phenyl]piperazine;mp. 175.6° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one;mp. 193.8° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2-ethyl-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one;mp. 178.3° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-5-methyl-2-propyl-3H-1,2,4-triazol-3-onemonohydrate; mp. 165.5° C.;

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 186° C.; and

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(5-propyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;mp. 140.9° C.

EXAMPLE XXIV

A mixture of 4 parts ofcis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]phenyl}-1-piperazinyl]benzenamine,0.5 parts of sodium azide, 1.08 parts of1,1',1"-[methylidynetris(oxy)]trisethane and 50 parts of acetic acid isstirred for 5 hours at 70° C. Another 0.5 parts of sodium azide and 1.08parts of 1,1',1"-[methylidynetris(oxy)]trisethane are added and stirringat 70° C. is continued for 15 hours. The reaction mixture is cooled andpoured onto a mixture of potassium carbonate and water. The product isextracted with dichloromethane. The extract is dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (98:2 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from 1-butanol, yielding 2.1 parts (48%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-tetrazol-1-yl)phenyl]piperazine;mp. 192.5° C.

EXAMPLE XXV

To a stirred mixture of 5.7 parts ofcis-4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]phenyl}-1-piperazinyl]benzenamineand 100 parts of acetic acid are added 1.5 parts oftetrahydro-2,5-dimethoxyfuran at 50° C. The whole is stirred andrefluxed for 5 minutes. The reaction mixture is poured onto crushed iceand the whole is neutralized with a sodium hydroxide solution 50%. Theproduct is extracted with dichloromethane. The extract is treated withactivated charcoal. The latter is filtered off and the filtrate isevaporated. The residue is crystallized from 1-butanol, yielding 3.3parts (52%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-pyrrol-1-yl)phenyl]piperazine;mp. 188.9° C.

In a similar manner there is also prepared:

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(1H-pyrrol-1-yl)phenyl]piperazine;mp. 184.9° C.

EXAMPLE XXVI

A mixture of 40 parts of ethanimidamide hydrochloride, 20 parts ofcis-N-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}hydrazinecarboxamide,40 parts of sodium acetate and 90 parts of N,N-dimethylformamide isstirred and heated for 4 hours at 130° C. The reaction mixture is cooledand 100 parts of water are added. The precipitated product is filteredoff, washed with water and with 2-propanol, and crystallized from1-butanol, yielding 9 parts (44%) ofcis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-5-methyl-3H-1,2,4-triazol-3-one2-propanolate (2:1); mp. 295.7° C.

In a similar manner there are also prepared:

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 275.6° C.; and

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 255° C.

EXAMPLE XXVII

A mixture of 1.31 parts of 2-bromopropane, 5 parts ofcis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-oneand 100 parts of dimethyl sulfoxide is stirred at 50° C. and 0.4 partsof sodium hydride dispersion 50% are added. After stirring for 1 hour at50° C., another 1.31 parts of 2-bromopropane and 0.4 parts of sodiumhydride dispersion 50% are added and stirring is continued for 1 hour at50° C. The reaction mixture is cooled and poured onto water. The productis extracted with dichloromethane. The extract is washed with water,dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (99:1 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone, yielding 2 parts (37%) ofcis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-(1-methylethyl)-3H-1,2,4-triazol-3-one;mp. 222.1° C.

In a similar manner there are also prepared:

cis-2-butyl-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-3H-1,2,4-triazol-3-one;mp. 199.2° C.; and

cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-5-ethyl-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one;mp. 170.4° C.

EXAMPLE XXVIII

Following the procedure described in Example XIX there are alsoprepared:

trans-3-[4-{4-[2-(5-bromo-2-thienyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine;

4-[4-{4-[2-(2-chloro-6-methylphenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine;

4-[4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine;

3-[4-{4-[2-(5-chloro-2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinyl]benzenamine.

EXAMPLE XXIX

Following the procedure described in Example XX there are also prepared:

cis-1-{4-[2-(3-ethoxyphenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(3-methyl-1H-pyrrol-1-yl)phenyl]piperazine;

1-{3-[2-(1H-imidazol-1-ylmethyl)-2-(2-thienyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[3-(4-phenyl-1H-pyrrol-1-yl)phenyl]piperazine;

trans-1-{4-[2-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(1H-pyrrol-1-yl)phenyl]piperazine;

cis-1-{3-[2-(4-bromo-2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-4-[4-(2,5-diethyl-1H-pyrrol-1-yl)phenyl]piperazine;

4-[3-(4-methyl-1H-pyrazol-1-yl)phenyl]-1-{4-[2-(2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

trans-1-{4-[2-(5-bromo-2-thienyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(2-ethylthio-4-phenyl-1H-imidazol-1-yl)phenyl]piperazine;

cis-4-[4-(5-ethyl-2-mercapto-1H-imidazol-1-yl)phenyl]-1-{3-[2-phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine;

1-{4-[2-(4-bromo-2-ethoxyphenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[3-(5-phenyl-1H-1,2,4-triazol-1-yl)phenyl]piperazine;

trans1-{3-[2-(5-chloro-2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[2-(3-methylthio-5-pentyl-4H-1,2,4-triazol-4-yl)phenyl]piperazine;

4-{4-[4-{4-[2-(2,6-diethoxyphenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-phenylmethyl-3H-1,2,4-triazol-3-one;

cis4-{4-[4-{4-[2-(2-(2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-methyl-5-phenylmethyl-3H-1,2,4-triazol-3-one.

EXAMPLE XXX

Following the procedure described in Example XXI there are alsoprepared:

1-{4-[2-(4-fluorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(5-methylthio-1H-tetrazol-1-yl)-phenyl]piperazine;

trans1-{4-[2-(5-chloro-2-thienyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-[4-(5-phenylethyl-1H-tetrazol-1-yl)phenyl]piperazine.

What is claimed is:
 1. A chemical compound having the formula ##STR68##and the pharmaceutically acceptable acid addition salts andstereochemically isomeric forms thereof, wherein:Q is a member selectedfrom the group consisting of CH and N; Ar is a member selected from thegroup consisting of phenyl, thienyl, halothienyl and substituted phenyl,said substituted phenyl having from 1 to 3 substituents eachindependently selected from the group consisting of halo, lower alkyl,lower alkyloxy and trifluoromethyl.
 2. A chemical compound selected fromthe group consisting ofcis-4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]benzenamineand the pharmaceutically acceptable acid addition salts andstereochemically isomeric forms thereof.
 3. A chemical compound selectedfrom the group consisting ofcis-4-[4-[4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl]-1-piperazinyl]benzenamineand the pharmaceutically acceptable acid addition salts andstereochemically isomeric forms thereof.